An insulin signaling pathway couples feeding and nutritional status in mammals to the rate and mode of metabolism in most tissues of the animal. We have shown that an insulin-like signaling pathway regulates longevity and metabolism in C. elegans. This is reminiscent and may be mechanistically related to the longevity increase caused by caloric restriction in mammals. Thus the genetic components of the C. elegans insulin signaling pathway may be key components of a mammalian longevity determining pathway. Mammalian orthologs of many of these genes have been identified. We have shown that insulin signaling in the C. elegans nervous system is key to longevity regulation. We will identify which neurons are the centers of longevity control and will use genetics and RNA interference to identify signals from those neurons to the target tissues that degenerate during the aging process. We will determine the molecular identity of the worm genes revealed by the extensive genetic and genomic analysis proposed in the grant, search for human homologues of those genes, and test whether these human proteins in fact can function in the C. elegans insulin-like signaling pathway, that is, are functional homologues. In addition to their possible roles in longevity control, the insulin signaling genes we have identified by C. elegans genetics may reveal components of insulin signaling in mammals that are important for the understanding and eventual treatment of diabetes. Diabetes is a common disease that affects the production or response to insulin, causing devastating metabolic dysregulations. The molecular basis of the defective insulin response in the adult onset or type II diabetes is unknown. It is clear that it is at least in part a genetic disease. Saturation genetic analysis of the homologous C. elegans metabolic control pathway has revealed genes that act downstream of the insulin-like receptor as well as other neuroendocrine signals that converge with insulin. The products of the genes we have identified may be targets for pharmaceutical development of diabetes therapies.